HUT75871A - Azole derivatives and pharmaceutical compositions thereof - Google Patents

Description

The present invention relates to novel azole derivatives of formula (I), and salts, hydrates and solvates thereof: In the formula (I), R ¹ and R ^{2 have the} same or different meaning: hydrogen, lower alkyl or phenyl optionally substituted by halogen. means;

A, B and D independently represent a group of formula (IV) or a nitrogen atom;

X and Y are each independently a single bond, a methylene group, an oxygen atom, a group of formula (V) or a group of formula (VI);

R ³ and R 4 each independently represent hydrogen or lower alkyl; and n is 0, 1 or 2.

The compounds of the present invention inhibit the lysis of the steroid 17-20 and are therefore useful in the prevention and treatment of the following diseases: prostate cancer, prostate hypertrophy, female hermaphroditism, breast cancer, hyperplasia, uterine myositis, endometrial inflammation, and mammary disease.

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83460-6015 MR / JG

Representative:

DANUBIA Patent and Trademark Office Ltd.

Budapest

PUBLICATION LITERATURE

International Application Number: PCT / JP94 / 01593 International Publication Number: WO 95/09157

AZOL DERIVATIVES AND PHARMACEUTICAL PRODUCTS CONTAINING THESE COMPOUNDS

The present invention relates to novel azole derivatives, their pharmaceutically acceptable salts and pharmaceutical compositions containing such compounds which are useful as inhibitors of steroid 17-20 lyase.

A steroid known as the 17-20 home steroid is known to play a role in the living organism from cholesterol to androgen formation as the last step in the latter's biosynthetic formation. The steroid 17-20 lyase utilizes 17a-OH pregnenolone and 17a-0H progesterone, which have a carbon substituent at the 17p position and are formed from cholesterol, and the steroid 17-20 lyase is cleaved by the carbon at the 17-position of the carbon substituent. and 20-carbon, thereby promoting the formation of various types of androgens. Consequently, inhibition of the enzyme activity of the steroid 17-20 lyase allows inhibition of androgen production and inhibition of estrogen production, the latter being synthesized from androgen as a substrate, and prevention and treatment of various diseases in which androgen is

83460-6015 MR / JG • ·

-2-estrogens play a role as excitatory factors. Prostate cancer, prostate hypertrophy, female hermaphroditism, breast cancer, hair swelling, endometrial cancer, endometrial inflammation and mammary disease may be mentioned as examples of the role of androgen and estrogen.

On the other hand, it has been fully demonstrated that lowering androgen levels in blood serum is useful for treating prostate cancer, and in clinical practice, testicular removal or the use of an LH-RH agonist or androgen antagonist is widespread. However, physiologically unacceptable testicular depletion and LH-RH agonists are unable to inhibit androgenic activity except for the androgen secreted by the gonads, and LH-RH agonists temporarily cause redness. As for androgen antagonists, it has become known in recent years that their effect is reduced by mutation of the androgen receptor. Consequently, inhibition of androgen activity at its receptors (total androgen blocking) has been suggested in the literature, and efforts have been made to use it in combination with an LH-RH agonist and an androgen antagonist.

A compound capable of inhibiting the enzyme steroid 17-20 lyase is considered to be an agent capable of total androgen blocking by potent blocking of its androgen function and thus a promising agent for the treatment of, for example, prostate cancer. In addition, a steroid 17-20 lyase inhibitor is believed to be a much more potent therapeutic agent for the treatment of prostate hypertrophy and to have far less side effects than therapeutic agents that inhibit androgen alone, in view of reducing estrogen activity.

As steroid 17-20 lyase inhibitors, steroid-type and non-steroid-type compounds have been synthesized. Non-steroid steroid 17-20 lyase inhibitors include, for example, (1H-imidazol-1-yl) methyl-substituted imidazole derivatives disclosed in Japanese Patent Publication No. 64-85975 (Kokai), wherein a substituted benzimidazolyl group is

The -3-bicyclic group and an imidazolyl group are linked by a carbon atom of a methine group or a methylene group.

However, the compounds of the present invention described below contain a fused tricyclic moiety which is structurally different from the compounds mentioned and is also novel in their pharmacological activity as, as will be described later, an excellent steroid 17-20 lyase and concomitantly with testosterone synthesis inhibitors.

However, compounds having an imidazolyl group and a fluorenyl group as a fused tricyclic group are known as antifungal compounds from Japanese Patent Application Laid-Open No. 47-1471 (Kokai) and aromatase-inhibiting compounds from U.S. Patent No. 4,757,082.

However, the structure of the compounds of the present invention differs from the structure of said compounds in that the benzene ring of the fused tricyclic group is attached via an carbon atom.

In addition, no mention was made of the inhibitory effect of steroid 17-20 lyase on the latter known compounds.

As shown above, various attempts have been made, however, the development of excellent steroid 17-20 lyase inhibitors remains a medical field.

It has now been found that the compounds of formula I and their pharmaceutically acceptable salts possess excellent steroid 17-20 lyase inhibitory activity. In the general formula (I)

R ¹ and R ^{2, with the} same or different meanings, are hydrogen, lower alkyl or phenyl optionally substituted by halogen;

A, B and D independently represent a group of formula (IV) or a nitrogen atom;

-4X and Y are each independently a single bond, a methylene group, an oxygen atom, a group of formula (V) or a group of formula (VI);

R ^{3 is} independently hydrogen or lower alkyl; and n is 0, 1 or 2.

Preferred compounds of the present invention are those azole derivatives or pharmaceutically acceptable salts thereof, wherein, in formula I, R ¹ and R ³ are each independently hydrogen or lower alkyl;

X is a single bond or a group of formula (V);

Y is a methylene group, a group of formula V or a group of formula VI.

More preferred are azole derivatives or pharmaceutically acceptable salts thereof wherein X is a single bond and Y is methylene. The most preferred azole derivative of the invention is 1- [1- (9H-fluoren-2-yl) ethyl] -1H-imidazole or pharmaceutically acceptable salts thereof.

The invention further relates to pharmaceutical compositions containing as an active ingredient an azole derivative of the formula (I) or a pharmaceutically acceptable salt thereof. Such pharmaceutical compositions of the present invention are useful as steroid 17-20 lyase inhibitors and are useful in the treatment and prevention of prostate cancer, prostate hypertrophy, female hermaphroditism, breast cancer, hair loss, uterine cancer, endometrial inflammation and breast disease.

Preferred examples of the pharmaceutical compositions of the present invention include those which contain 1- [1- (9H-fluoren-2-yl) ethyl] -1H-imidazole or a pharmaceutically acceptable salt thereof as an active ingredient.

It is characteristic of the chemical structure of the compounds of the invention that it

the nitrogen atom of the azole ring is attached via a carbon atom to the fused tricyclic group containing X and Y substituents. In addition, the pharmacological properties of the compounds of the present invention are that they exhibit a particularly high inhibitory activity over the imidazolylmethylimidazole derivatives known as steroid 17-20 lyase inhibitors disclosed in Japanese Patent Publication No. 64-85975 (Kokai).

In the following, the substituents of the compounds of formula (I) are described in more detail.

Unless otherwise indicated, the term "lower" refers to carbon chains having 1 to 6 carbon atoms.

Lower alkyl groups in the compounds of the present invention include straight or branched chain alkyl groups having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethyl-butyl, 1,2-dimethyl-butyl, 2,2-dimethyl-butyl, 1,3-dimethyl-butyl, 2,3-dimethyl-butyl, 3,3-dimethyl butyl, 1-ethyl-butyl, 2-ethyl-butyl, 1,1,2-trimethyl-propyl, 1,2,2-trimethyl-propyl, 1-ethyl-methyl-propyl and ethyl-2-methyl-propyl. Of these groups, we prefer C 1-4 groups such as methyl, ethyl, propyl, isopropyl and butyl, more preferably methyl and ethyl and most preferably methyl.

The term "halogen optionally substituted phenyl" refers to phenyl groups which may be substituted at any position by a halogen atom. Examples of halogen atoms include fluorine, chlorine, bromine and iodine, or any combination thereof. The number of halogen atoms is preferably 1.2 or 3. Consequently, the term "halogen optionally substituted phenyl" means, for example, the following groups: fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, difluorophenyl ,, dichlorophenyl, dibromophenyl, bromochlorophenyl, trichlorophenyl, bromodichlorophenyl, dibromochloro · · · · · · · · • · ··· · ·

-6-phenyl, trichlorophenyl, bromodichlorophenyl, dibromochlorophenyl and bromochlorofluorophenyl. Of these groups, chlorophenyl is preferred, and 3-chlorophenyl is more preferred.

Examples of the group represented by formula (VII) include imidazolyl, 1H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1H-1. , 2,3,4-tetrazolyl or 3H-1,2,3,4-tetrazolyl, of which imidazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl are preferred. and imidazolyl is even more preferred.

Illustrative examples of the group (VIII) include: biphenylenyl (group IX), 9,10-dihydro-anthracenyl group (group X), carbazolyl group (group XI), dibenzofuryl group (XII) ), dibenzothienyl (XIII), phenothiazinyl (XIV), phenoxathienyl (XV), phenoxazinyl (XVI), phenazinyl (XVII), dibenzo-p-dioxinyl group (XVIII), thiantrenyl group (XIX), acridanyl group (XX), xanthenyl group (XXI), thioxanthenyl group (XXII), fluorenyl group [XXIII], Dibenzothiophenyl 9-oxide [XXIV], Thioxanthenyl-5,5-Dioxide [XXV], 10-Methylthiazinyl [XXVI], 9 -ethylcarbazolyl [( XXVII). Of the listed groups, fluorenyl, dibenzothienyl, dibenzofuryl, dibenzothiophenyl-9-oxide, phentiazinyl and 10-methylpentiazinyl are preferred, 2-fluorenyl is more preferred.

The compounds of the invention may form salts. Such salts include pharmaceutically acceptable salts. Examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydrogen iodide, sulfuric acid, nitric acid or phosphoric acid, as well as organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, malonic acid, acid,

- Acid addition salts with malic acid, tartaric acid, citric acid, methanesulphonic acid or ethane sulphonic acid.

Depending on the nature of the substituents, the compounds of the invention may form salts with alkali metals or alkaline earth metals (e.g., sodium, potassium, magnesium or calcium), ammonia, or organic amines (e.g., triethylamine).

Depending on the nature of the substituents, the compounds of the present invention may contain asymmetric carbon atoms and may form optical isomers for the asymmetric carbon atom or diastereomers when the compound contains 2 or more asymmetric carbon atoms. All such isomers in their isolated form, as well as mixtures thereof, are within the scope of the invention. In some cases, the compounds of the invention may form different types of hydrates and solvates, or may be polymorphic. All such compounds, either in isolated form or as mixtures thereof, are considered to be within the scope of the invention.

The compounds of the invention and their salts may be prepared by various synthetic chemical methods depending on their basic structure and the nature of their substituents.

Following are some representative examples of methods for preparing the compounds of the invention.

Production Method 1

This method of preparation is illustrated in Scheme 1. In Scheme 1, E is a leaving group such as halogen or sulfonyloxy, while A, B, D, X, Y, R.1 are as previously defined.

Examples of sulfonyloxy groups include methanesulfonyloxy, ethanesulfonyloxy or p-toluenesulfonyloxy.

Step 1 may be carried out, for example, by reacting a compound of formula (IIa) in the form of a secondary or tertiary alcohol with a halogenation or sulfonic acid ester, and then reacting the resulting reactive derivative in step 2 with an azole of formula (III). «« · · • · · · · · · · · · · · · · · · · · ·.

With a derivative -8 to produce a target compound of formula (I). In this case, the reaction of Step 2 can be carried out without isolation of the intermediate obtained in Step 1. In step 1, the halogenation may be carried out, for example, by reacting the alcohol with a molar equivalent or excess of a halogenating agent, such as thionyl chloride, phosphorus pentachloride or oxalyl chloride. Alternatively, the sulfonic acid ester may be prepared by reacting the alcohol with, for example, p-toluenesulfonyl chloride or methanesulfonyl chloride.

The reaction of Step 1 may be carried out at temperatures between room temperature and the reflux temperature of the solvent used. Inert solvents such as halogenated hydrocarbons (e.g. methylene chloride, chloroform or 1,2-dichloroethane) and aromatic hydrocarbons (e.g. benzene or toluene) may be used as the solvent.

In step 2, the azole compound of formula (III) used, such as imidazole or triazole, acts as a base, so there is no need to use other bases. In this case, the azole compound (III) is used in an amount of 2 to 10 times the amount of the alkyl derivative (IIb) and the reaction is carried out at a temperature of 50 ° C to 150 ° C. In such cases, the azole may also serve as a solvent, but organic solvents which are inert to the reactants, such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, toluene or acetonitrile, may be used as co-solvents.

Alternatively, the reaction of Step 2 may be carried out at a temperature of 0 ° C to 100 ° C, and addition of an alkyl derivative of formula IIb and an equivalent or excess amount of a compound of formula III such as imidazole or triazole by. Examples of suitable bases include sodium hydride, potassium hydride, potassium bis (trimethylsilyl) amide, sodium amide, n-butyllithium, and the like. · · «» * · «·« · · · «« · · · ♦ · ··· · · · · · · ·.

-9Potassium tert-butylate, metal sodium, sodium methylate or sodium ethylate. When a base is used, the reaction is carried out in an inert organic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, toluene or acetonitrile.

Production Method 2

This method is illustrated in Scheme 2. In this scheme, A, B, D, X, Y, R 1 and R 4 are as previously defined.

Thus, the compounds of formula (I) of the present invention can be prepared by reacting an azole compound of formula (III) with a compound of formula (Ha) using a dehydrating condensing agent such as 1,1'-carbonyldiimidazole.

The reaction may be carried out at temperatures between the ice-cooling temperature and the reflux temperature of the solvent used, such as dichloromethane, chloroform, dichloroethane or tetrahydrofuran.

The preparation methods described above may also be carried out using a protecting group when, for example, X and Y are imino.

Examples of protecting groups include dimethylsulfonyl, benzenesulfonyl, ρ-toluenesulfonyl, acetyl or Boc. Removal of the protecting group may be accomplished by any of the methods well known in the art.

A compound of formula (I) of the present invention thus obtained can be isolated and purified in the form of the free compound or a salt, hydrate or solvate thereof. Pharmaceutically acceptable salts of the compounds of formula I according to the invention may be prepared by any of the methods well known in the art for the preparation of such salts.

Isolation and purification can be accomplished by conventional chemical methods such as extraction, fractional crystallization, or various types of fractional chromatography.

The optical isomers may also be prepared in the form of stereochemically pure isomers by use of appropriate starting compounds or by resolution of a resulting racemic product, for example by converting such a compound to a diastereomeric salt with a commonly used optically active base followed by optical resolution.

The compounds of the invention, as mentioned above, inhibit the activity of steroid 17-20 lyase, an enzyme involved in the production of androgen from cholesterol in the living body. Consequently, the compounds of the present invention can be used to treat or prevent various diseases in which androgen and estrogen (the latter formed by androgen) act as stimulating factors. Examples of these types of diseases include prostate cancer, prostate hypertrophy, female hermaphroditism, breast cancer, hair follicles, uterine myxoma, endometrial inflammation, and breast disease.

The therapeutic utility of the compounds of the present invention can be demonstrated by the following experiments.

(1) Measuring the inhibitory effect of steroid 17-20 lyase in rats

The experiments may be performed according to the method described in J. Steroid Biochem., 33 (6), 1191-1195 (1989).

One testis male Wistar rat was excised and homogenized and centrifuged to isolate microsomes. Microsomal protein was 50 pg, ΙμΜ [l, 23H] -i7 _the _hidroxi-progesterone (5.55 · 10 ^ dpm) and a test compound dissolved in 100 μΐ 50 mM phosphate buffer (pH 7.4) and the resulting solution is mixed with NADPH solution and incubated at 37 ° C for 60 minutes. Subsequently, 400 μΐ of a 2: 3 v / v mixture of methanol and tetrahydrofuran was added to the mixture, followed by centrifugation. In the resulting supernatant liquid, the radioactivity of the substrate and its products (androstenedione and testosterone) was measured by high performance liquid chromatography on a column equipped with a radioactive isotope detector.

- 11 »» ·· «(English abbreviation: HPLC) was performed to test the activity of the test compound in inhibiting steroid 17-20 lyase.

(2) In vivo measurement of testosterone synthesis inhibitory activity in rats

The assay was performed as described in J. Steroid Biochem., 32 (6), 781-788 (1989).

Each test compound is orally administered to fast 10-week-old male Wistar rats under fasting conditions. One hour after administration of the test compound, 60 ng / rat LH-RH was administered by intramuscular injection to enhance testosterone synthesis. After another hour, the rat is bled after decapitation and the testosterone concentration in the resulting serum is measured by radioactive isotope assay to determine testosterone synthesis inhibitory activity.

Experimental results

The results of experiments with the compounds of the invention are given below.

(1) Measuring the inhibitory effect of steroid 17-20 lyase in rats

In testicular microsomes of rats, steroid 17-20 lyase inhibitory activity was calculated as the IC50 using the method described in Experimental Method (1) when the following results are listed in Table 1.

Table 1

Serial number of example compound for test compound Concentration of active ingredient that reduces steroid 17-20 lyase activity by 50% Example 2 IC 50 = 4.0 nM Example 4 5.0 nM Example 8 5.7 nM Example 10 6.9 nM control Compound 420 nM

- 12 Note that the control compound mentioned in Table 1 is the compound of Example 187 described in Japanese Patent Publication No. 64-85975 (Kokai).

The control compound is assayed in the same manner, but the compounds of the present invention show activity of 60 times or more.

(2) In vivo measurement of testosterone synthesis inhibitory activity in rats

In the above experimental method (2), in vivo activity in inhibition of testosterone synthesis in rats is expressed as the percentage inhibition of testosterone synthesis relative to the control group, with each test compound or control compound at a dose of 1 mg / kg or 10 mg / kg. give it. The results are summarized in Table 2.

Table 2

Serial number of the example of the test compound Dose Rate of inhibition of testosterone synthesis Example 2 1 mg / kg 86.3% Example 7 1 mg / kg 78.4% Example 8 1 mg / kg 73.0% control Compound 10 mg / kg 47.0%

It is noted that the control compound mentioned in Table 2 is the compound of Example 187 of Kokai Publication No. 64-85975.

Thus, the compounds of the present invention exhibit a significantly better inhibitory effect on the inhibition of testosterone synthesis in rats at tenth of the dose of the control compound.

Formulations of the present invention containing a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof, may be prepared using conventional carriers and / or other excipients.

The pharmaceutical compositions may be administered orally or parenterally in the form of tablets, powders, granules, granules, capsules, pills, solutions, injections or suppositories, for example.

Although the dosage used in a particular case is determined by a number of factors, such as the symptoms of the disease, and the age, sex and weight of the patient being treated, it is generally 0.1 mg to 100 mg, preferably 0.1 mg to 10 mg daily for oral administration to adults. the dose is administered either once or several times, or in the case of parenteral administration in adults, the dose is 0.1 mg to 100 mg once or several times a day or by continuous intravenous injection for 1-24 hours a day. It will be appreciated by those skilled in the art that lower doses than those mentioned above may be effective in some cases, since the daily dosage as mentioned above may vary depending on a number of factors.

Compositions of the invention suitable for oral administration may be used, for example, in the form of tablets, powders or granules. Such solid formulations may contain at least one active ingredient with at least one inert carrier and / or other excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, fine crystalline cellulose, starch, polyvinylpyrrolidone or magnesium metasilicate. Conventionally, such a formulation may contain, in addition to the inert diluent, other additives, such as lubricants (such as magnesium stearate), disintegrants (e.g., calcium carboxymethylcellulose), stabilizers (e.g., lactose), and solubilizing agents (e.g., glutamic acid). In some cases, the tablets or pills may be coated with a film that is soluble in the stomach or intestine, such as a film made from sucrose, gelatin, hydroxypropylcellulose or hydroxypropylmethylcellulose phthalate.

Liquid preparations suitable for oral administration

Include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, which may contain conventional inert diluents such as purified water or ethanol. In addition to the inert diluent, these compositions may contain further adjuvants, such as solubilizers or solubilizers, wetting or suspending agents, and flavoring agents, sweeteners, flavoring agents, and antiseptics. Injections suitable for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions, and emulsions. Suitable diluents for aqueous solutions and suspensions include, for example, distilled water and saline for injection. Suitable diluents for non-aqueous solutions and suspensions include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), alcohols (e.g., ethanol), and Polysorbate 80. Such compositions may also contain adjuvants such as tonicity adjusting agents, antiseptics, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (e.g., lactose), solubilizing agents, or solubilizers. Such compositions may be sterilized by bacterial filtration, admixing with bactericides, or irradiation. Alternatively, a sterile solid composition may be prepared first by reconstitution with sterile water or other sterile injectable solvent prior to use.

The following examples are intended to illustrate the invention.

Example 1 (1) To a solution of 1.05 g of 2- (1-hydroxyethyl) -9H-fluorene in 15 ml of methylene chloride is added 1.1 ml of thionyl chloride and a catalytic amount of Ν, Ν-dimethyl formamide, and the resulting mixture was stirred at room temperature for 30 minutes and then refluxed for one hour. Evaporation of the solvent under reduced pressure gave 2- (1-chloroethyl) -9H-fluorene.

(2) The thus obtained 2- (1-chloroethyl) -9H-fluorene was dissolved in 20 ml of N, N-dimethylformamide and 2.72 g of imidazole was added thereto. After stirring at 100 ° C for 2 hours, the solvent was removed under reduced pressure. Water was added to the residue, followed by extraction with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: chloroform: methanol = 200: 1). The crude crystals isolated from the eluate thus obtained were recrystallized from a mixture of ethyl acetate and diethyl ether to give 0.6 g of 1- [1- (9H-fluoren-2-yl) ethyl] -1H-imidazole.

Analysis results based on the formula:

Found: C, 83.04; H, 6.19; N, 10.76.

Found: C, 83.14; H, 6.16; N, 10.80.

Nuclear Magnetic Resonance Spectrum (CDCl3, internal standard: TMS): δ 1.91 (3H, d, J = 7Hz), 3.86 (2H, s), 5.42 (1H, q, J = 7Hz), δ, 97 (1H, s), 7.10 (1H, s), 7.19 (1H, d, J = 8Hz),

7.29 - 7.33 (2H, m), 7.38 (1H, t, J = 7Hz), 7.54 (1H, d, J = 7Hz), 7.6 (1H, s),

7.3 - 7.8 (2 H, m).

Example 2

8.88 g of 1- [1- (9H-fluoren-2-yl) ethyl] -1H-imidazole are dissolved in ethyl acetate and 15 ml of 4N hydrochloric acid in ethyl acetate are added to the resulting solution under ice-cooling. The crystals thus precipitated were collected by filtration and washed with ethyl acetate to give 9.95 g of 1- [1- (9H-fluoren-2-yl) ethyl] -1H-imidazole hydrochloride.

Analysis results for CjgHp ^ Cl:

Found: C, 72.84; H, 5.77; N, 9.44; Cl, 11.95;

Found: C, 72.57; H, 5.72; N, 9.40; Cl, 11.79.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, internal standard: TMS): δ 1.96 (3H, d, J = 7Hz), 3.94 (2H, s), 5.92 (1H, q, J = 7Hz) ), 7.32-7.41 (2H, m), 7.49 (1H, d, J = 8Hz), 7.60 (1H, d, J = 8Hz), 7.69 (1H, s) ), 7.73 (1H, s), 7.91-7.95 (3H, m), 9.48 (1H, s).

- Example 163

In the same manner as in Example 1, but starting from α- (9H-fluoren-2-yl) -3-chlorobenzyl alcohol and imidazole, 1- [3-chloro-α- (9H-fluoren-2-yl) - benzyl] -1H-imidazole can be prepared.

Analysis results for C23H17N2Cl:

Found: C, 77.41; H, 4.80; N, 7.85; Cl, 9.93;

Found: C, 77.53; H, 4.80; N, 7.76; Cl, 10.5.

Nuclear Magnetic Resonance Spectrum (CDCl3, internal standard: TMS): δ 3.87 (2H, s), 6.56 (1H, s), 6.88 (1H, s), 7.01 (1H, d, J = 7Hz), 7.13 (2H, d, J = 6Hz), 7.28-7.40 (4H, m), 7.46 (1H, s), 7.54 (1H, d, J = 7Hz), 7.75-7.79 (2H, m), 7.14 (1H, s), 7.26 (1H, s).

Example 4

In the same manner as in Example 1, but starting from 2- (9H-fluoren-2-yl) -propanol and imidazole, 1- [1- (9H-fluoren-2-yl) -1-methylethyl] -1H- imidazole can be prepared.

Analysis results for C19H18N2:

Found: C, 83.18; H, 6.61; N, 10.21;

Found: C, 83.21; H, 6.80; N, 10.21.

Nuclear Magnetic Resonance Spectrum (CDCl3, internal standard: TMS): δ 1.97 (6H, s), 3.85 (2H,

s), 6.95 (1H, s), 7.12-7.3 (2H, m), 7.21 (1H, s), 7.30 (1H, t, J = 7Hz), 7, 37 (1H, t, J = 7Hz), 7.53 (1H, d, J = 8Hz), 7.68-7.72 (2H, m), 7.76 (1H, d, J = 7 Hz).

Examples 5 and 6 (1) To a solution of 2- (1-hydroxy) ethyl-9H-fluorene (0.8 g) in methylene chloride (10 ml) was added with cooling (0.83 ml) and a catalytic amount of Ν, Ν-dimethyl formamide, and the resulting mixture was stirred at room temperature for 30 minutes and then refluxed for one hour. The solvent was then evaporated under reduced pressure to give 2- (1-chloroethyl) -9H-fluorene.

(2) The thus obtained 2- (1-chloroethyl) -9H-fluorene is mixed with 1.31 g of 1,2,4-triazole and the resulting mixture is added at 120 [deg.] C. without additional solvent.

- Heat for 1730 minutes. After cooling, water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated and the resulting residue was purified by column chromatography on silica gel. After eluting with chloroform / methanol (50: 1), the crude crystals were recrystallized from diethyl ether / ethyl acetate. There was thus obtained 0.24 g of 1- [1- (9H-fluoren-2-yl) ethyl] -1H-1,2,4-triazole (Example 5).

The crude crystals isolated from the eluate (50: 1, chloroform / methanol) were then recrystallized from ethyl acetate / diethyl ether to give 4- [1- (9H-fluoren-2-yl) ethyl] 0.25 g. 4H-1,2,4-triazole (Example 6) is obtained.

(Example 5)

Analysis results for C17H15N3:

Found: C, 78.13; H, 5.79; N, 16.08;

Found: C, 78.32; H, 5.80; N, 16.12.

Nuclear Magnetic Resonance Spectrum (CDCl3, internal standard: TMS): δ 1.99 (3H, d, J = 7Hz), 3.88 (2H, s), 5.63 (1H, q, J = 7Hz), 7.28 - 7.33 (2H, m), 7.38 (1H, t, J = 7Hz), 7.44 (1H, s), 7.54 (1H, d, J = 7Hz), 7.76-7.78 (2H, m), 7.99 (1H, s), 8.08 (1H, s).

(Example 6)

Analysis results for C17H15N3:

Found: C, 78.13; H, 5.79; N, 16.08;

Found: C, 78.29; H, 5.75; N, 16.25.

Nuclear Magnetic Resonance Spectrum (CDCl3, internal standard: TMS): δ 1.96 (3H, d, J = 7Hz), 3.88 (2H, s), 5.48 (1H, q, J = 7Hz), 7.22 (1H, d, J = 8Hz), 7.32-7.35 (2H, m), 7.33 (1H, s), 7.39 (1H, t, J = 7Hz), 7.55 (1H, d, J = 8Hz), 7.77-7.79 (2H, m), 8.22 (2H, s).

7-13. Examples 1 to 9 may be prepared in a manner analogous to that described in Example 1.

Example 7

- [(9H-Fluoren-2-yl) methyl] -1H-imidazole

Starting compounds: 2- (hydroxymethyl) -9H-fluorene and imidazole

F isico-chemical parameters:

Melting point: 193-194 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl 3, Internal Standard: TMS): δ 3.86 (2H, s), 5.17 (2H, s), 6.94 (1H, s), 7.11 (1H, s), δ , 19 (1H, d, J = 8Hz), 7.29 - 7.33 (2H, m), 7.38 (1H, t, J = 7Hz), 7.54 (1H, d, J = 7Hz), 7.58 (1H, s), 7.74-7.78 (2H, m).

Example 8

- [1- (Dibenzothiophen-3-yl) ethyl] -1H-imidazole

Starting compounds: 3- (1-hydroxyethyl) dibenzothiophene and imidazole

Physico-chemical characteristics:

Melting point: 103-105 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl3, internal standard: TMS): δ 1.96 (3H, d, J = 7Hz), 5.51 (1H, q, J = 7Hz), 6.98 (1H, s), 7.12 (1H, s), 7.24 (1H, dd, J = 8Hz, 2Hz), 7.46 7.48 (2H, m), 7.61 (1H, s), 7.66 (1H, s), 7.84-7.86 (1H, m), 8.10-8.15 (2H, m).

Example 9

- [1- (Dibenzofuran-3-yl) ethyl] -1H-imidazole

Starting compounds: 2- (3-dibenzofuranyl) propanol and imidazole

Physico-chemical characteristics:

M.p. 98-99 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl3, internal standard: TMS): δ 1.95 (3H, d, J = 7Hz), 5.51 (1H, q, J = 7Hz), 6.97 (1H, s), 7.11 (1H, s), 7.14 (1H, d, J = 8Hz), 7.33-7.48 (3H, m), 7.56 (1H, d, J = 8Hz), 7.65 (1H, s), 7.90 (1H, d, J = 8Hz), 7.93 (1H, d, J = 8Hz).

Example 10

2- [1- (1H-Imidazol-1-yl) ethyl] phenothiazine monooxalate

Starting compounds: 2- (1-hydroxyethyl) phenothiazine and imidazole

Physico-chemical characteristics:

- 19 • · · · · · · · · · · · · · · ·

Mass spectrum (m / z): 293 (M ⁺ ) (free base).

Nuclear Magnetic Resonance Spectrum (DMSO-d6, internal standard: TMS): δ 1.76 (3H, d, J = 7Hz), 5.53 (1H, q, J = 7Hz), 6.50 (1H, s), 6.60-6.75 (3H, m), 6.83-6.99 (3H, m), 7.32 (1H, s), 7.50 (1H, s), 8.51 (1H, s), 8.62 (1H, s).

Example 11

2 - [[1- (1H-Imidazol-1-yl) ethyl] -10-methyl] phenothiazine monofumarate

Starting compounds: 2- (1-hydroxyethyl) -10-methylphenothiazine and imidazole Physico-chemical characteristics:

Analysis results for C22H21N3O4S:

Calculated: C, 62.40; H, 5.00; N, 9.92; S, 7.57;

Found: C, 62.02; H, 5.07; N, 9.82; S, 7.17.

Melting point: 193-194 ° C.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, internal standard: TMS): δ 1.79 (3H, d, J = 7Hz), 3.30 (3H, s), 5.50 (1H, q, J = 7Hz) ), 6.63 (2H, s), 6.84-6.88 (2H, m), 6.94-6.97 (3H,

m), 7.11-7.15 (2H, m), 7.21 (1H, t, J = 9Hz), 7.33 (1H, s), 7.91 (1H, s).

Example 12

- [1- (9H-Fluoren-2-yl) -butyl] -1H-imidazole

Starting compounds: 1- (9H-fluoren-2-yl) butanol and imidazole

Physico-chemical characteristics:

Melting point: 73-74 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl 3, Internal Standard: TMS): δ 0.98 (3H, t, J = 7Hz), 1.31 1.38 (2H, m), 2.16-2.30 (2H, m) ), 3.86 (2H, s), 5.18 (1H, t, J = 8Hz), 6.98 (1H, s), 7.08 (1H, s), 7.22 (1H, d) , J = 8Hz), 7.30-7.38 (3H, m), 7.53 (1H, d, J = 7Hz), 7.64 (1H, s), 7.73 (1H, d) , J = 8Hz), 7.76 (1H, d, J = 8Hz).

Example 13 1 - [(9H-Fluoren-2-yl) (phenyl) methyl] -1H-imidazole

Starting compounds: a- (9H-fluoren-2-yl) -benzyl alcohol and imidazole Physico-chemical characteristics:

141-142 ° C.

-20NMR (CDCl3, internal standard: TMS): δ 3.86 (2H, s), 6.59 (1H, s), 6.89 (1H, s), 7.11 - 7.40 (10H) , m), 7.45 (1H, s), 7.53 (1H, d, J = 7Hz), 7.76 (2H, dd, J = 7Hz, 7Hz).

Example 14

To 1.1 g of 2- (1-chloroethyl) -9H-fluorene is added 1.64 g of 1H-1,2,3-triazole and the resulting mixture is heated at 120 ° C for 30 minutes. After cooling, water was added and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue thus obtained was purified by column chromatography over silica gel using chloroform as eluent. The crude crystals isolated from the eluate thus obtained were recrystallized from ethyl acetate to give 0.62 g of 1- [1- (9H-fluoren-2-yl) ethyl] -1]-1,2,3-triazole.

Physico-chemical properties:

Melting point: 160-162 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl3, internal standard: TMS): δ 2.05 (3H, d, J = 7Hz), 3.87 (2H, s), 5.92 (1H, q, J = 7Hz), 7.26 - 7.39 (3H, m), 7.44 (1H, s), 7.48 (1H, d, J = 1Hz), 7.54 (1H, d, J = 8Hz), 7.70 (1H, d, J = 1Hz), 7.74-7.78 (2H, m).

Example 15

To a solution of 0.2 g of 1- [1- (dibenzothiophen-3-yl) ethyl] -1H-imidazole (0.2 g) in chloroform (5 ml) was gradually added 0.18 g of 3-chlorine under ice-cooling. perbenzoic acid and the resulting reaction mixture was stirred at the same temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the chloroform layer was separated, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting residue was purified by column chromatography over silica gel (eluent: chloroform: methanol = 100: 1). The oily substance separated from the eluate was dissolved in acetone and mixed with 40 mg of fumaric acid and the resulting mixture was heated until the fumaric acid was dissolved. After cooling, it precipitated

The crystals were washed with acetone to give 90 mg of 3- [1- (1H-imidazol-1-yl) ethyl] dibenzothiophene-5-oxide monofumarate.

Physico-chemical properties:

Mass Spectrum (m / z): (FAB): 295 (M + H) ⁺ (free base):

Nuclear Magnetic Resonance Spectrum (DMSO-d6, internal standard: TMS): δ 1.88 (3H, d, J = 7Hz), 5.71 (1H, q, J = 7Hz), 6.63 (2H, s), 6.97 (1H, s), 7.39 (1H, s), 7.57-7.63 (2H, m), 7.71 (1H, t, J = 8Hz), 7, 93 (1H, s), 8.01 - 8.13 (4H, m).

Example 16 (1) To a solution of 9-phenylsulfonyl-2- (1-hydroxyethyl) carbazole (0.621 g, 1.77 mmol) in methylene chloride at room temperature was added 0.26 mL (3.54 mmol). thionyl chloride and a catalytically effective amount of DMF, and the resulting reaction mixture was refluxed for 1.5 hours. The solvent was evaporated under reduced pressure and the resulting residue was stirred with ethyl acetate. The resulting mixture was washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. 9- (phenylsulfonyl) -2- (1-chloroethyl) carbazole is obtained.

(2) To a solution of the thus obtained 9-phenylsulfonyl-2- (1-chloroethyl) carbazole in 8 ml of dimethylformamide was added imidazole (1.21 g, 17.7 mmol) at room temperature, and the reaction mixture was stirred at 120 ° C for 2.5 hours. The reaction mixture was partitioned between ethyl acetate and distilled water, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 120: 1, v / v). The resulting eluate was isolated as an oily substance (0.456 g, 1.14 mmol, 61%) 9- (phenylsulfonyl) -2- [1- (1H-imidazol-1-yl) ethyl] carbazole.

Physico-chemical properties:

·· ····

Nuclear Magnetic Resonance Spectrum (DMSO-d6, internal standard: TMS): δ 1.91 (3H, d, J = 7Hz), 5.79 (1H, q, J = 7Hz), 7.01 (1H, s), 7.35 (1H, s), 7.39-7.74 (8H, m), 7:91 (1H, s), 8.01 (1H, s), 8.09-8.12 (2H, m), 8.27 (1H, d, J = 8Hz).

(3) From the thus obtained 9- (phenylsulfonyl) -2- [1- (1H-imidazol-1-yl) ethyl] carbazole 0.436 g (1.09 mmol), 50 ml ethanol and 10 ml 2 The aqueous solution of sodium hydroxide solution was refluxed for 4 hours with stirring, then the volatile components were evaporated under reduced pressure. The resulting residue was stirred with chloroform and the resulting mixture was washed with a saturated aqueous sodium chloride solution. The organic phase is then dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: chloroform: methanol = 100: 1). The crude crystals isolated from the eluate thus obtained were finally recrystallized from ethyl acetate to give 0.174 g of 2- [1- (1H-imidazol-1-yl) ethyl] carbazole.

Physico-chemical properties:

Melting point: 157-158 ° C.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, internal standard: TMS): δ 1.87 (3H, d, J = 7Hz), 5.69 (1H, q, J = 7Hz), 6.93 (1H, s ), 7.10 - 7.47 (6H, m), 7.85 (1H, s), 8.06 - 8.09 (2H,

m), 11.25 (1H, s).

The chemical structures of the compounds prepared in the above examples are given in the following table. In this table, the bonding position refers to the position in which the group (VII) is attached to the group (VIII).

»·· · compounds of the formula I

example row- number THE B D R ¹ R ² binding state X Y Salt First CH CH CH CH? H 2 binding ch? Second CH CH CH CH? H 2 binding ch? hydrochloride Third CH CH CH 3-chlorophenyl H 2 binding CH? 4th CH CH CH ch? H 2 binding CH? hydrochloride 5th CH N CH CH? H 2 binding CH? 6th N CH CH CH? H 2 binding CH? 7th CH CH CH H H 2 binding CH? 8th CH CH CH CH? H 2 binding S 9th CH CH CH CH? H 2 binding 0 - 10th CH CH CH CH? H 2 S NH oxalate 11th CH CH CH CH? H 2 S N-CH fumarate 12th CH CH CH CH9CH9CH7 H 2 binding N-CH 13th CH CH CH phenyl H 2 binding CH? 14th CH CH N CH? H 2 binding CH2 15th CH CH CH CH? H 2 binding SALT fumarate 16th CH CH CH CH? H 2 binding NH

In addition to the compounds described in the examples above, the following compounds of the present invention are described. Since these compounds can be prepared by the methods and procedures described above, it will be understood by those skilled in the art that no specific examples are required.

THE Serial number of compound THE B D R ¹ R ² binding state X Y First CH CH CH CH7CH7 H 2 binding CH7 Second CH CH CH CH7CH7CH7 } CH 2 binding CH7 Third CH CH CH 4-chlorophenyl H 2 binding CH7 4th CH CH CH 3-bromophenyl } CH 2 binding CH7 5th CH CH CH } CH } CH 2 binding S 6th CH CH CH } CH } CH 2 S NH 7th CH CH CH } CH H 1 binding CH7 8th CH CH CH ch ₃ H 1 binding S 9th CH CH CH } CH H 1 S NH 10th CH CH CH CH7CH7CH} H 3 binding CH7 11th CH CH CH CH7CH7CH} H 3 binding S 12th CH CH CH CH7CH7CH} H 3 S NH 13th CH CH CH CH7CH} H 4 binding CH7 14th CH CH CH 2-chlorophenyl H 2 binding CH7 15th CH CH CH } CH H 2 binding binding 16th CH CH CH } CH H 2 CH7 CH7 17th CH CH CH } CH H 3 S NH 18th CH CH CH } CH H 3 S 0 19th CH CH CH } CH H 2 NH 0 20th CH CH CH } CH H 2 NH NH 21st CH CH CH } CH H 2 0 0 22nd CH CH CH } CH H 2 S S 23rd CH CH CH } CH H 2 CH7 NH 24th CH CH CH } CH H 2 CH7 0 25th CH CH CH } CH H 2 CH7 S

• a · aa

THE Serial number of compound THE B D R ¹ R ² binding state X Y 26th CH CH CH CH H 2 binding NH 27th CH CH CH phenyl H 2 binding NH 28th CH CH CH 3-chlorophenyl H 2 binding NH 29th CH CH CH } CH CH3 2 binding NH 30th N CH CH CH H 2 binding NH 31st CH N CH CHG H 2 binding NH 32nd CH CH CH CH7CH9CH7 H 2 binding NH 33rd CH CH N CHG H 2 binding NH 34th CH C CHG CH CH3 H 2 binding NH

In the following, an example of a pharmaceutical composition of the present invention is described, more particularly an example of an oral composition. The composition of this preparation is as follows:

Komponens_Mennyiség

Tablet

compounds of the formula I according to the invention 1.0 mg lactose 76.4 mg cornstarch 19.3 mg hydroxypropyl cellulose 3.0 mg magnesium stearate 0.3 mg Sub-total 100 mg

♦ ··

-26Bevonat

hydroxypropyl methylcellulose 2910; 2.9 mg polyethylene glycol 6000 0.4 mg titanium oxide 1.6 mg talc 0.1 mg Sub-total ^5m S

Total: 105 mg

The following describes the preparation of a tablet containing 1 mg of the active ingredient.

7 g of one of the compounds of formula I according to the invention are mixed with 534.8 g of lactose in a polyethylene bag and the resulting mixture is pulverized in a sample mill made by Hosokawa Micron, Japan. 541.8 g of this powdered mixture is uniformly mixed with 135.1 g of corn starch in a fluidization granulation coating machine manufactured by the Japanese company Ohkawara Seisakusyo. 210 g of 10% hydroxypropyl cellulose solution is sprayed into the apparatus to effect granulation. After drying, the resulting granules are screened through a 20 mesh sieve, then mixed with 2.1 g of magnesium stearate and then converted to 100 mg tablets on a rotary tabletting machine manufactured by Japanese company Hata Tekkosyo using a die having a diameter of 6 mm. . 7.8 R. A coating solution containing 20.3 g of hydroxypropylmethylcellulose, 2.8 g of polyethylene glycol (6000) is sprayed on the tablets thus obtained in a coating machine manufactured by the Japanese company Freund Sangyo. It contains 11.2 g of titanium oxide and 0.7 g of talc. This gives film-coated tablets each containing 5 mg of coating material.

-27 * ·· · »» «·« · • • * * «« «« «« «

Patent claims:

Claims (8)

Patent claims: 1. Azole derivatives of the formula (I) and salts, hydrates and solvates thereof - in the formula (I) R ¹ and R ^{2, with the} same or different meanings, are hydrogen, lower alkyl or phenyl optionally substituted by halogen; A, B and D independently represent a group of formula (IV) or a nitrogen atom; X and Y are each independently a single bond, a methylene group, an oxygen atom, a group of formula (V) or a group of formula (VI); R ³ and R 4 each independently represent hydrogen or lower alkyl; and n is 0, 1 or 2. Compounds according to claim 1, characterized in that R 1 and R ² independently represent hydrogen or lower alkyl, X is a single bond or Y is methylene, Y is methylene or a group of formula (VI). Compounds according to claim 1, characterized in that X is a single bond and Y is a methylene group. 4. The compound of claim 1 which is 1- [1- (9H-fluoren-2-yl) ethyl] -1H-imidazole. 5. A pharmaceutical composition comprising an active ingredient An azole derivative of the formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof. 6. A steroid 17-20 lyase inhibitor, characterized in that the active ingredient is an azole derivative of the formula (I) according to claim 1 or a medicament. -28 contains a pharmaceutically acceptable salt thereof. The steroid 17-20 lyase inhibitor according to claim 6, characterized in that it is an agent for the prevention and / or treatment of prostate cancer, prostate hypertrophy, female hermaphroditism, breast cancer, hair follicles, uterine cancer, endometrial inflammation and breast disease. The steroid 17-20 lyase inhibitor of claim 6 or 7, wherein the active ingredient is 1- [1- (9H-fluoren-2-yl) ethyl] -1H-imidazole or a pharmaceutically acceptable salt thereof. . The agent, instead of the notifier: Imre Molnár Patent Attorney Our Act Number: 83460-5194 - JG PUBLICATION LETTER (X) ί PUBLICATION LITERATURE